Imatinib (STI571) plus hydroxyurea: Safety and efficacy in pre-treated, progressive glioblastoma multiforme (GBM) patients (pts)

Abstract

1550 Background: Imatinib (I) is a tyrosine kinase inhibitor of Bcr-Abl, platelet-derived growth factor receptors (PDGF-Rs) and the Kit receptor, with remarkable clinical efficacy in chronic myeloid leukaemia and gastrointestinal stromal tumours (GIST). Many malignancies of the brain including GBM express these receptors, yet preliminary results of previous studies have shown a low response rate when used as single agent therapy. Hydroxyurea (H) freely penetrates the brain and cerebrospinal fluid (CSF), and in fact may modulate the blood-brain barrier to facilitate uptake of other drugs. For this reason, we suggested that the combination H with I could potentiate it's activity in GBM. Methods: From June 2001 to November 2003, an exploration of combination therapy with H plus I in 26 GBM pts refractory to multiple prior therapies, including radiation therapy and chemotherapy containing ACNU and temozolomide, was started. Pts were treated with I (400 mg) and H (1000 mg) as continuous daily, oral dosing and followed by clinical examination and magnetic resonance imaging (MRI) every 6 weeks. Results: Fourteen patients are currently evaluable for safety and efficacy. ECOG-performance status at the start of therapy was 1–2, the median age was 40 yrs (31–68), and WHO classification of tumours IV only. Results after a median treatment period of 29 weeks (4–104) were one complete response (CR) lasting 12 months, 4 partial responses (PR) lasting a median of 8 months (1–24), 4 stable disease (SD) for a median of 12 months (3–23) and 5 progressive disease (PD). There were no grade 3 or 4 toxicities. Twelve deaths occurred, 1 pt with PR and 1 pt with SD died of pulmonary embolism, and 10 pts died of PD. The median progression free survival (PFS) was 29 weeks and median overall survival (OS) was 37 weeks. Two pts remain alive without progression for 16 and 24 months, respectively. Conclusions: In summary, combination therapy with I and H was well tolerated and effective in this group of recurrent, refractory GBM pts, with a response rate of 36% and a PFS greater than 6 months. Based on these results, a Phase II study with I plus H in GBM has been started. No significant financial relationships to disclose.